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Updated: Nov 17, 2025

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
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The doxorubicin-induced cell motility network is under the control of the ceramide-activated protein phosphatase 1

Daniel Canals1, Silvia Salamone1, Bruno Jaime Santacreu1,2

  • 1Department of Medicine, Stony Brook University, Stony Brook, NY, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|February 14, 2021
PubMed

Insights

Sublethal doxorubicin enhances cancer cell migration by altering plasma membrane ceramide levels. Protein phosphatase 1 alpha (PP1 alpha) dephosphorylates cytoskeletal proteins, promoting this migratory phenotype and potentially worsening metastasis.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Sublethal doses of doxorubicin can enhance cancer cell migration.
  • Plasma membrane ceramide, generated by neutral sphingomyelinase 2 (nSMase2), mediates this effect.
  • The specific molecular mechanisms underlying doxorubicin-induced cancer cell migration remain incompletely understood.

Purpose of the Study:

  • To investigate the role of protein phosphatase 1 (PP1) family members in doxorubicin-induced cancer cell migration.
  • To identify the specific PP1 isoform involved and its downstream targets.
  • To elucidate the mechanism by which ceramide and PP1 alpha influence cytoskeletal protein regulation and cell migration.

Main Methods:

  • Bioinformatics analysis to construct a functional interaction network based on phosphoproteomics data.
  • Identification of protein phosphatase 1 alpha (PP1 alpha) as the key enzyme.
  • Utilizing phospho mutants of ezrin and Scrib to assess the impact of dephosphorylation on cell migration.

Main Results:

  • Protein phosphatase 1 alpha (PP1 alpha) was identified as the specific PP1 isoform mediating doxorubicin-induced cell migration.
  • A functional interaction network revealed downstream substrates of ceramide-PP1 alpha signaling.
  • Dephosphorylation of ezrin at T567 and Scrib at S1378/S1508 by PP1 alpha was sufficient to enhance cancer cell migration.

Conclusions:

  • Reduced doses of doxorubicin dysregulate cytoskeletal proteins via a ceramide-PP1 alpha pathway, leading to enhanced cancer cell migration.
  • This mechanism provides a potential explanation for doxorubicin's role in exacerbating cancer metastasis in animal models.
  • Targeting this pathway could offer novel therapeutic strategies to prevent metastasis.
Keywords:
ceramidedoxorubicinmigrationphosphatasesphingomyelinase

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